The overall objective of this proposal is to test the hypothesis that scar anisotropy is a desired structural feature that contributes importantly to the normal function of adjacent myocardium. The applicant will examine for the roles that mechanical stretch, preexisting extracellular matrix and the upregulation of Transforming Growth Factor-b1 (TGF-b1) play in defining the anisotropic structure of the myocardial scar. Initial studies are designed to define the normal spatial gradient of finite deformation in myocardium adjacent to the healing scar in a pig model of myocardial infarction. To directly test the hypothesis that the unique structure of the scar influences function in adjacent myocardium the applicant proposes to modify scar structure by manipulating local levels of TGF-b1 during healing. Additional studies to be performed in the pig model of infarction and in vitro in cultured cardiac fibroblasts will test for the roles that mechanical deformations, preexisting matrix and TGF-b1 have on defining scar structure and function. Clinically, it is known that the timely reperfusion of acutely ischemic myocardium can reduce infarct size and preserve left ventricular function. This approach has become the treatment of choice within hours of coronary occlusion. There is evidence that strength and collagen content of reperfused scars differs from that of permanently occluded myocardium. However, beyond these observations little is known about scar structure and function of bordering myocardium in the setting of coronary occlusion and reperfusion. Thus, as a third aim of the proposal the applicant will examine in infarcted-reperfused pig myocardium the structural features and mechanical properties of scar tissue as well as function in bordering myocardium.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL043617-07
Application #
2735159
Study Section
Cardiovascular and Pulmonary Research A Study Section (CVA)
Project Start
1989-07-01
Project End
2001-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
7
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Moreno-Ulloa, Aldo; Nogueira, Leonardo; Rodriguez, Alonso et al. (2015) Recovery of Indicators of Mitochondrial Biogenesis, Oxidative Stress, and Aging With (-)-Epicatechin in Senile Mice. J Gerontol A Biol Sci Med Sci 70:1370-8
Spinale, Francis G; Villarreal, Francisco (2014) Targeting matrix metalloproteinases in heart disease: lessons from endogenous inhibitors. Biochem Pharmacol 90:7-15
Gutiérrez-Salmeán, Gabriela; Ortiz-Vilchis, Pilar; Vacaseydel, Claudia M et al. (2014) Acute effects of an oral supplement of (-)-epicatechin on postprandial fat and carbohydrate metabolism in normal and overweight subjects. Food Funct 5:521-7
Gutierrez-Salmean, Gabriela; Ciaraldi, Theodore P; Nogueira, Leonardo et al. (2014) Effects of (-)-epicatechin on molecular modulators of skeletal muscle growth and differentiation. J Nutr Biochem 25:91-4
Aguilar, Hugo; Fricovsky, Eduardo; Ihm, Sang et al. (2014) Role for high-glucose-induced protein O-GlcNAcylation in stimulating cardiac fibroblast collagen synthesis. Am J Physiol Cell Physiol 306:C794-804
Moreno-Ulloa, Aldo; Romero-Perez, Diego; Villarreal, Francisco et al. (2014) Cell membrane mediated (-)-epicatechin effects on upstream endothelial cell signaling: evidence for a surface receptor. Bioorg Med Chem Lett 24:2749-52
Yamazaki, Katrina Go; Andreyev, Aleksander Y; Ortiz-Vilchis, Pilar et al. (2014) Intravenous (-)-epicatechin reduces myocardial ischemic injury by protecting mitochondrial function. Int J Cardiol 175:297-306
Ramirez-Sanchez, Israel; De los Santos, Sergio; Gonzalez-Basurto, Silvia et al. (2014) (-)-Epicatechin improves mitochondrial-related protein levels and ameliorates oxidative stress in dystrophic ?-sarcoglycan null mouse striated muscle. FEBS J 281:5567-80
Li, Ai-Hsien; Liu, Peter P; Villarreal, Francisco J et al. (2014) Dynamic changes in myocardial matrix and relevance to disease: translational perspectives. Circ Res 114:916-27
DeCoux, Ashley; Lindsey, Merry L; Villarreal, Francisco et al. (2014) Myocardial matrix metalloproteinase-2: inside out and upside down. J Mol Cell Cardiol 77:64-72

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